Phenylpropanolamine is a sympathomimetic compound administered orally as an anorectic and as a nasal decongestant. The compound has two chiral centers, as shown in the following structural formula: ##STR1##
This results in four optical isomers, listed as follows with their common names and absolute configurations:
______________________________________ Isomer .alpha. .beta. ______________________________________ (+)-norephedrine R S (-)-norephedrine S R (+)-norpseudoephedrine S S (Cathine) (-)-norpseudoephedrine R R ______________________________________
The .beta. center is optically stronger and is responsible for the observed rotation. The .alpha. center, however, is primarily responsible for determining the physiological effect of the compound. An R configuration at this position gives a compound with predominantly peripheral effects (vasoconstriction, etc.), whereas compounds with an S configuration have greater central nervous system (CNS) activity. Since the anorectic effect is CNS-mediated, one would expect (-)-norephedrine and (+)-norpseudoephedrine to be the most potent in this regard. (+)-Norpseudoephedrine is a naturally occurring substance found primarily in the shrub Catha edulis and is used orally in Europe for its anorectic properties at a dose of about 40-50 mg/day. A racemic mixture of (+)-norephedrine and (-)-norephedrine, generally referred to as phenylpropanolamine (PPA), is marketed domestically as an anorectic at a dose of about 50-75 mg/day, and as a nasal decongestant at a dose of about 75-225 mg/day, preferably about 150-200 mg/day for adults.
Transdermal delivery of drugs has become increasingly well known as the technology to manufacture transdermal delivery systems advances. Transdermal devices such as reservoir, matrix and adhesive patches are well known. The advantages of transdermal delivery are also well known and include the practical advantages of ease of use and greater patient compliance and the pharmacological advantage of sustained blood levels. It has been reported by A. S. Michaels et al in AIChE J., 21 (1975), pgs. 985-996, that ephedrine, an N-methyl derivative of PPA, penetrates cadaver skin at a rate of 300 mg/cm.sup.2 /hr. While the article does not state whether "ephedrine" refers to the racemate or an isomer, it is believed to refer to (-)-ephedrine, since that isomer is the conventional commercially available form. A more recent article, J. C. Blosser et al, Eur. J. Pharmacology, 134 (1987) pgs. 97-103 indicates that when administered orally, the enantiomers of PPA showed a 4-5 fold difference in potency, the order being (+)-norpseudoephedrine, (-)-norephedrine, (-)-norpseudoephedrine and (+)-norephedrine (highest to lowest).